Field of the Invention
The present invention relates generally to active pharmaceutical agents and method for their preparation and more specifically to an amorphous form of trisodium sacubitril valsartan and processes for the preparation thereof.
Background of the Invention
Sacubitril valsartan, also known as LCZ696, is a co-crystallized complex of valsartan and sacubitril in a 1:1 molar ratio. Chemically, valsartan is known as (S)-3-methyl-2-(N-{[2′-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid and sacubitril is known as 4-{[(2S,4R)-1-(4-biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid. LCZ696 consists of 6 valsartan anions, 6 sacubitril cations, 18 sodium cations, and 15 molecules of water. Sacubitril valsartan is marketed under the trade name ENTRESTO® by Novartis. The reduced formula of the sacubitril valsartan, as included in the ENTRESTRO® product, is shown below as Formula-I as a single valsartan molecule with a single sacubitril molecule together with three sodium anions and 2.5 water molecules.
Sacubitril is a neprilysin inhibitor and valsartan is an angiotensin II receptor blocker. ENTRESTO® is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.
U.S. Pat. No. 8,877,938 discloses a supramolecular complex of trisodium sacubitril valsartan hemipentahydrate in crystalline form.
The present invention provides amorphous trisodium sacubitril valsartan as well as a process for the preparation thereof. Amorphous trisodium sacubitril valsartan may provide different advantages in a variety of capacities, for example, in formulation, stability of the form, stability of the formulation, and in pharmacokinetic profiles. Within the context of the present disclosure, Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] will be referred to as “trisodium sacubitril valsartan.”